PROJECT SUMMARY Placebo response is an important and poorly understood phenomenon of treatment response. A large and variable placebo response has been evident in decade?s long placebo-controlled double blind clinical trials that tested various treatments for alcohol use disorders (AUD). Large placebo effects complicate detection of quantifiable treatment effects for investigational medications, especially for the modestly effective psychiatric drugs. Placebo response arise from a complex interaction of patient, clinical trial staff, and treatment environment factors. Because the placebo response is intricate, complex and variable among individuals, it is challenging to identify these individuals prior to enrollment in a clinical trial. The proposed project seeks to explore the utility of genomics to identify placebo responders in phase ?? AUD treatment trials. To date, to the best of our knowledge, comprehensive genomic studies have not been conducted to assess genetic variation in relation to outcomes of AUD treatment or placebo response. Genomic analyses require large sample sizes that are not easy to gather in small to medium scale clinical trials conducted with treatment seeking individuals with an AUD or other drug use disorder. To address this issue, we will leverage the resources from six completed and two ongoing NIAAA-funded phase ?? AUD treatment trials. We will first examine changes in patterns of drinking among the enrolled treatment-seeking individuals with AUD, during treatment with a placebo (Aim ?). We will then explore how these changes in drinking affect expression of genes, perusing the entire genome of each individual (Aim ??). The genes whose expression levels are found to be changed according to a person?s drinking behavior or how frequent the person was able to abstain from alcohol, will be fine- combed to identify DNA sequence (genetic) variations that rendered them susceptible to varying amounts of alcohol (Aim ???). Next, we will explore whether these genetic variations and the expression patterns of their genes, can predict placebo response (as measured by abstinence rates) in populations with AUD together with other psychiatric conditions (cocaine addiction and PTSD; Exploratory Aim ?). Finally, we will explore whether the identified genetic variants and genes are expressed in the same manner in those who have received an active medication (ondansetron/topiramate/naltrexone) for the treatment of their AUD (Exploratory Aim ??), which may help us understand the placebo component embedded within response to an active medication, at a molecular level. In summary, our proposed project is conceptually and methodologically innovative in exploring genetic variations by examining gene expression differences associated with amounts of drinking during placebo treatment. As the first study to characterize genomics of placebo response in phase ?? AUD trials, findings will provide a wealth of information for future translational research and propagate personalized medicine. Harnessing the placebo response and knowing how to optimize it will allow us to: a) improve overall outcomes; b) determine who is in need of additional treatment, and c) characterize the therapeutic index (efficacy/side effects) for particular subgroups with AUD.